Project Summary Obesity is now established as a potential cause for colon cancer. While the underlying mechanisms mediating the obesity-colon cancer link are not well understood, increasing evidence supports that Insulin resistance resulting from long-term energy imbalance and subsequent perturbation of metabolic homeostasis and insulin signaling pathways form the core of obesity-related colon carcinogenesis. Genetic variations within genes in key insulin and growth factor signaling pathways may, or in combination with obesity, drive the development of colon cancer, but have been little studied. The fact that obesity is escalating as an epidemic worldwide makes the exploration of the mechanistic connections between obesity and colon cancer a pressing public health and research priority. Therefore, we propose a genetic epidemiologic study of the relation of colon cancer with obesity and candidate genes in four critical insulin and related growth factor signaling pathways: 1) phosphatidylinositol-3 Kinase/protein kinase B (PI3K/AKT) signaling cascade; 2) AMP-activated protein kinase (AMPK) pathway; 3) mitogen-activated protein (MAP) kinase pathway; and 4) peroxisome proliferators-activated receptors (PPARs). Each of these pathways plays an important role linking increased adiposity to colon carcinogenesis and model systems indicate that crosstalk occurs among them. We will use both conventional statistical approaches and a novel hierarchical model to comprehensively evaluate obesity and adult weight gain, candidate gene polymorphisms and haplotypes, and their potential joint and interactive effects on colon cancer. The unifying theme of this proposal is that obesity and candidate gene variants within these pathways may act alone or jointly to drive colon carcinogenesis. This study builds upon an ongoing population-based case-control study where epidemiologic data and DNA samples from 1,250 incident colon cancer cases and 1,500 population controls has already being collected. This relatively large study population will be readily available and allow us to dissect complex gene-gene and gene-obesity interactions to gain in- depth understanding of mechanistic link between obesity and colon carcinogenesis.